Potent antiretroviral therapy (ART) including nucleoside reverse transcriptase inhibitors (NRTI) substantially reduces morbidity and mortality due to human immunodeficiency virus type 1 (HIV) infection and acquired immunodeficiency syndrome (AIDS), but is frequently limited by mitochondrial toxicity. Peripheral neuropathy (PN) is a common, debilitating toxicity that is often irreversible. Variation in the onset, character, and severity of NRTI-associated PN strongly suggests host genetics play a role, but an understanding of this role has been elusive. As life-saving ART becomes increasingly available in resource-limited settings, we can anticipate a future "epidemic" of PN in new populations unless improved understanding and technology can be rapidly translated to these settings. The overarching hypothesis of this proposal is that improved understanding of associations between variation in the human mitochondrial genome and ART-induced PN through the application of state-of-the-art technology (high- throughput whole mitochondrial genome sequencing) and computational resources (to include multifactor dimensionality reduction) can prevent this toxicity and ultimately improve long-term ART outcomes. The proposed work will expand on the existing base of knowledge regarding mitochondrial effects of ART, and will explore novel areas by addressing two specific aims: 1) To characterize mitochondrial DNA (mtDNA) polymorphisms, including multilocus genetic interactions, that confer increased susceptibility to the development of symptomatic PN among HIV-infected individuals treated with NRTI-containing ART regimens; and 2) To characterize relationships between mtDNA polymorphisms and markers of neuronal and mitochondrial injury, including epidermal nerve fiber densities, serum lactate concentrations, and peripheral blood mtDNA content. We propose to address these aims through nested case-control studies using stored DNA and available data from 800 HIV-infected clinical study participants. Information from these studies will allow clinicians to better individualize HIV therapy, avoiding debilitating, often irreversible, and costly complications, thus having important applications in both affluent and resource-limited parts of the world. Results from this study will also advance the field of "mitochondrial medicine", having broad application across other scientific disciplines and for other human diseases. [unreadable] [unreadable] [unreadable]